Bartsch H
German Cancer Research Center (DKFZ), Division of Toxicology and Cancer Risk Factors, Heidelberg, Germany.
Mutat Res. 1996 Jun;340(2-3):67-79. doi: 10.1016/s0165-1110(96)90040-8.
Sensitive methods for quantifying DNA adducts from (i) benzo[a]pyrene (BP), (ii) alkylation exposure, and (iii) etheno(epsilon)-DNA adduct-forming chemicals were developed and applied to humans and animal models. The aims were to identify hitherto unknown sources and mechanisms of exogenous and endogenous DNA damage, to examine the effect of drug polymorphism on BP adduct levels, and to develop QSAR between tumorigenic potency, heritable genetic damage and structural elements of alkylating carcinogens (Vogel and Nivard (1994) Mutation Res., 395, 13-32). (i) BP-DNA adducts: An HPLC/fluorimetry assay suitable for measuring (+)-anti-BP-diol-epoxide (BPDE) adducts in human tissues and white blood cells (WBC) was developed (Alexandrov et al. (1992) Cancer Res., 52, 6248-6253). In smokers, a positive correlation was found between pulmonary CYP1A1-related catalytic activity (AHH) and the level of lung BPDE-DNA adducts. In coke oven workers, an enhancing effect of smoking on BPDE-adduct levels in WBC was demonstrated (Rojas et al. (1995) Carcinogenesis, 16, 1373-1376). (ii) 3-Alkyladenines (3-alkAde): Alkylating carcinogens form 3-alkAde adducts in DNA which depurinate to yield 3-alkAde in urine, for which a detection method was developed (Friesen et al. (1991) Chem. Res. Toxicol., 4, 102-106; Prevost et al. (1990) Carcinogenesis, 11, 1747-1751), using immunoaffinity purification and GC-MS analysis. The usefulness of 3-alkAde analysis for the determination of the whole-body dose of alkylating agents derived from exogenous and endogenous sources was demonstrated. (iii) Etheno-DNA adduct-forming agents: Etheno(epsilon)-DNA base adducts (epsilon A, epsilon dC, epsilon dG) are promutagenic DNA lesions that are formed by occupational (vinyl halides) and environmental (urethane) carcinogens. An ultrasensitive detection method was developed (Nair et al. (1995) Carcinogenesis, 16, 613-617), based on immunoaffinity purification and 32P-postlabelling of epsilon-nucleoside 3'-monophosphates. Liver DNA from unexposed rats, mice and from human samples contained background levels of epsilon dA and epsilon dC (Bartsch et al. (1994) Drug. Metab. Rev., 26, 349-371). As formation of epsilon dA and epsilon dC adducts by lipid peroxidation products was demonstrated (El Ghissassi et al. (1995) Chem. Res. Toxicol., 8, 278-283), they may serve as markers for oxidative stress. Results from testing this hypothesis are presented.
开发了用于定量（i）苯并[a]芘（BP）、（ii）烷基化暴露以及（iii）乙烯基（ε）-DNA加合物形成化学物质产生的DNA加合物的灵敏方法，并将其应用于人类和动物模型。目的是识别迄今未知的外源性和内源性DNA损伤的来源和机制，研究药物多态性对BP加合物水平的影响，并建立致瘤潜力、遗传性基因损伤与烷基化致癌物结构元素之间的定量构效关系（Vogel和Nivard（1994年），《突变研究》，395卷，13 - 32页）。（i）BP-DNA加合物：开发了一种适用于测量人体组织和白细胞（WBC）中（+）-反式-BP-二醇环氧化物（BPDE）加合物的HPLC/荧光测定法（Alexandrov等人（1992年），《癌症研究》，52卷，6248 - 6253页）。在吸烟者中，发现肺部CYP1A1相关催化活性（AHH）与肺部BPDE-DNA加合物水平呈正相关。在炼焦炉工人中，证明了吸烟对白细胞中BPDE加合物水平有增强作用（Rojas等人（1995年），《癌变》，16卷，1373 - 1376页）。（ii）3-烷基腺嘌呤（3-alkAde）：烷基化致癌物在DNA中形成3-alkAde加合物，其脱嘌呤后在尿液中产生3-alkAde，为此开发了一种检测方法（Friesen等人（1991年），《化学研究毒理学》，4卷，102 - 106页；Prevost等人（1990年），《癌变》，11卷，1747 - 1751页），采用免疫亲和纯化和GC-MS分析。证明了3-alkAde分析对于确定外源性和内源性来源的烷基化剂全身剂量的有用性。（iii）乙烯基-DNA加合物形成剂：乙烯基（ε）-DNA碱基加合物（εA、εdC、εdG）是由职业（卤代乙烯）和环境（聚氨酯）致癌物形成的促诱变DNA损伤。基于免疫亲和纯化和ε-核苷3'-单磷酸的32P后标记，开发了一种超灵敏检测方法（Nair等人（1995年），《癌变》，16卷，613 - 617页）。未接触的大鼠、小鼠肝脏DNA以及人类样本中含有背景水平的εdA和εdC（Bartsch等人（1994年），《药物代谢评论》，26卷，349 - 371页）。由于已证明脂质过氧化产物可形成εdA和εdC加合物（El Ghissassi等人（1995年），《化学研究毒理学》，8卷，278 - 283页），它们可作为氧化应激的标志物。展示了对该假设进行测试的结果。
